The subject of the invention is a method for the production of isoflavanes from isoflavones.
Isoflavones, also referred to as isoflavonoids, are compounds of mostly yellow coloration, which are derivatives of isoflavones and thus flavonoids. Isoflavones are secondary compounds from plants, which, amongst others, play a role in the plants' defense from pathogens. The ground body of isoflavone is found in clover species. Some well-known isoflavones are daidzein, found as a glucoside of daidzin in soy flour, genistein from soy beans and red clover, prunetin from the bark of plum trees, biochanin A from chickpeas and clover, orobol, santal from sandle wood, red wood and other woods and pratensein from fresh red clover.
The isoflavone Daidzein [4′,7-dihydroxyisoflavone; 7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is found in soy and is thus part of many foods and dietary supplements. The isoflavane equol [4′,7-dihydroxyisoflavane; 3-(4-hydroxyphenyl)-7-chromanol] is produced in the intestinal flora after consumption of daidzein. Equol is thus part of the group of secondary plant metabolites. It is assumed that the conversion is carried out by streptococci, lactamid acid bacteria and bifido bacteria. After the consumption of foods which are rich in daidzein, equol is detectable in blood and urine. Equol has a mild estrogenic activity (0.1% of the activity of steroid-estrogens) and can bind to the estrogen receptors ERα and ERβ. Only about a third (Caucasian population) up to half (Japanese population) of humans can produce equol from daidzein. In humans who are capable of producing equol (“equol producers”), the cholesterol reducing and anti-inflammatory effect of a soy-rich diet is more pronounced compared to humans, which are not capable of producing equol. Especially for S-equal, various anti-proliferative influences were shown and documented in studies, for instance, with respect to tissue changes in the breast, which may occur in females during the menopause. Equol also inhibits DHT production in males due to interactions with the 5α reductase. It is assumed that DGT is a cause in the forming of prostate cancer in males. Since equol is produced only in the intestine from daidzein, it can not be isolated from natural products and has to be produced artificially. Various publications disclose ways of production by microbiological methods. In this respect, EP 1025850 discloses a composition in which equol is produced microbiologically from isoflavones from soy. Microbiological production processes are disadvantageous in many respects. For instance, they are prone to disturbances, because microorganisms may change and thus yield different products. The product process thus has to be continually supervised. Frequently, the microorganisms have to be killed and removed from the composition after the production is completed.
Thus, it was tried to produce equol by means of organic synthesis.
Muthyala et al., 2004, describe a method for the production of equol from daidzein. The method comprises a reduction of the 2,3-double bond and the keto group in the presence of a palladiumhydroxide-catalyst of the formula Pd(OH)2. A racemate is obtained, which is subsequently separated into R-equol and S-equol by means of chromatography (HPLC).
Heemstra et al., 2006, disclose an asymmetric synthesis of the chromane-ring by means of Evans-alkylation and intra molecular etherification according to Buchwald.
The WO 2007/016423 A2 discloses a method for the reduction of the 2,3-double bond and the 4-keto group, elimination of 4-OH-group under formation of a 3,4-double bond, synthesis of a specifically applicable iridium-catalyst and subsequent enantioselective reduction of the 3,4-double bond with the iridium catalyst.
Gharpure et al., 2008, disclose a method for the total synthesis of various isoflavanes and equol.
Methods for the reduction of benzopyranes with boron hydrides and diboranes are disclosed in Thakar et al., Indian J. of Chem., 1965, 74-77.
The advantageous effects of isoflavones and phytoestrogens such as equol are usually observed, if the compounds are consumed over an extended time period in significant amounts. Since the equol precursor daidzein is found in comparatively large amounts in soy, equol could be administered as a dietary supplement (food supplement, nutritional supplement). It would thus be highly desirable that equol is available by a simple production method, in large amounts and at low costs.
The known methods of organic synthesis have the disadvantage that they are relatively complicated and require special and costly reagents. A simple and cost-efficient production which could be the basis for supplying large parts of the population with a daily dosis, is not possible with these methods. The known methods are not appropriate for cost-efficient industrial production, because they require either expensive catalysts comprising precious metals or specific chiral compounds, which are difficult to synthesize, as catalysts or protective groups. Moreover, the known methods generally require a separation of enantiomers from a racemate, which significantly increases the workload and thus the costs of industrial production.